Introduction Chimeric Antigen Receptor (CAR) T cell therapy has revolutionized treatment for relapsed/refractory multiple myeloma (RRMM). The standard lymphodepletion (LDP) regimen is fludarabine and cyclophosphamide (Flu/Cy), but bendamustine has shown comparable efficacy and lower toxicity rates. Given the renal clearance dependency of fludarabine, bendamustine offers an alternative for patients (pts) with renal impairment. In this study we analyzed clinical data and CAR T cell dynamics following idecabtagene vicleucel (Ide-cel) or ciltacabtagene autoleucel (Cilta-cel) focusing on renal function and LDP regimen.

Methods Renal impairment was classified according to the 2012 chronic kidney disease (CKD) guidelines by Stevens et al. prior to LDP (day -5). Stage 1-2 was defined as none/mild CKD and 3a-5 as moderate/severe. Progression-free survival (PFS) was defined as the interval from CAR T infusion to progression, relapse, or death; overall survival (OS) as the time to death from any cause.Fisher's exact test was used for categorical and the Mann-Whitney U test for continuous variables. Survival probabilities were estimated using the Kaplan-Meier method, with subgroup comparisons by log-rank test. A Firth's penalized Cox regression modeled CKD status, CAR T product, LDP regimen, and their interaction. Neutrophil-based immune effector cell-associated hematotoxicity (N-ICAHT) was assessed according to the 2023 EHA and EBMT consensus grading, and thrombocyte-based ICAHT (T-ICAHT) was evaluated based on Rejeski et al. 2025. CAR T cell dynamics were analyzed via flow cytometry on day of LDP, day of infusion (day 0), and days 7, 14, 30, and 100 post-infusion. P-values <0.05 were considered statistically significant.

Results A total of 87 pts were included, with 53 presenting with none/mild CKD and 34 with moderate/severe CKD. 78 pts in the cohort received Flu/Cy and 9 received bendamustine. The distribution of LDP regimens differed significantly between pts with none/mild and moderate/severe CKD (p<0.001). Standard Flu/Cy was most frequently used in pts with none or mild CKD (96.2%) compared to 55.9% in those with moderate/severe CKD. In contrast, bendamustine and reduced-dose Flu/Cy were more frequently employed in pts with moderate/severe CKD (26.5% vs. 0% and 17.6% vs. 3.8%, respectively).

OS and PFS did not differ by CKD status (OS: p=0.93; PFS: p=0.82). Stratified by CAR T product, while no PFS difference by CKD was seen in Ide-cel-treated pts (p=0.46), pts treated with Cilta-cel with none/mild CKD had superior PFS (p=0.03). LDP regimen did not influence PFS (p=0.21). In line, Firth's model showed no association of CKD or LDP with PFS. There was a significant interaction between CKD status and CAR T product (HR 19.32, 95% CI 1.25–2176, p=0.03). Subgroup analysis confirmed Cilta-cel yielded better PFS than Ide-cel in none/mild CKD (p<0.001), but not in moderate/severe CKD.

Median absolute lymphocyte count (ALC) nadir occurred at day -1 with standard Flu/Cy (0.033 ×10⁹/L) and at day +1 with bendamustine (0.059 ×10⁹/L). At day of CAR-T infusion, the bendamustine group showed significantly higher median ALC values compared to Flu/Cy (p=0.027).

CAR T cell expansion kinetics showed no significant difference in respect to CKD status or LDP regimen. However, we observed that at day 7, pts treated with Cilta-cel and none/mild CKD had significantly higher CD4 CAR T cell percentages (proportion of CD3 CAR T cells) compared to those with moderate/severe CKD (p<0.001). This difference persisted at days 14 (p<0.001) and 30 (p<0.001).

Hematologic toxicities were compared between LDP regimens. Early N-ICAHT grades differed significantly between groups (p=0.002), and early absolute neutrophil count (ANC) nadir was significantly higher in the bendamustine cohort (p<0.001). While there was a significant difference in early T-ICAHT grades (p=0.01), no significant differences were observed regarding late N-ICAHT, early platelet nadir, late T-ICAHT, early anemia, early hemoglobin nadir, late anemia, as well as cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS).

Conclusion Our findings highlight the safety of bendamustine-based LDP and emphasize the prognostic value of renal function in Cilta-cel-treated pts, with the efficacy advantage of Cilta-cel over Ide-cel potentially attenuated in moderate/severe CKD due to competing risks such as frailty, early toxicity, or impaired cellular fitness.

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2025
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